The Comparative Effectiveness and Safety of Pharmacotherapies for the Treatment of Opioid Use Disorder in Pregnancy

摘要 妊娠期间阿片类药物使用障碍（OUD）的发生率在2010年期间大幅增加。 这反映了在一般人群中观察到的风险。目前的建议， 指南组的指导原则是OUD孕妇接受阿片类激动剂治疗（OAT）。OAT已 已被证明可以改善OUD女性的妊娠结局，因为它可以防止阿片类药物戒断 可能破坏胎儿健康的症状，并减少非法阿片类药物和其他物质的使用。 美沙酮历来是怀孕期间OUD治疗的支柱。然而，近年来， 丁丙诺啡的使用有所增加，目前与美沙酮的使用量大致相当。 美沙酮和丁丙诺啡具有不同的药理作用。这些人 治疗方法也不同。美沙酮是在联邦政府的监督下分发的- 规范的阿片类药物治疗计划相比之下，丁丙诺啡通常通过处方以处方形式分发。 常规办公室设置。丁丙诺啡也有两种制剂，作为单一产品和作为药物组合物。 与阿片类拮抗剂纳洛酮联合使用，旨在通过注射阻止滥用。比较 药物治疗妊娠期OUD的安全性和有效性数据非常 有限公司MOTHER试验表明，丁丙诺啡与不太严重的新生儿 戒断综合征与美沙酮相比关于丁丙诺啡和丁丙诺啡的比较安全性的数据 美沙酮与其他不良妊娠结局及对长期神经发育的影响 这类数据很少，而且存在一些潜在的偏见和局限性。的比较效益 丁丙诺啡和美沙酮在治疗中的保留和对产前护理充分性的影响 也没有被完全定义。对于那些规定丁丙诺啡在怀孕期间，使用的单产品 尽管误用的风险较高，但通常建议使用，因为有关安全性的数据很少。 包括纳洛酮的组合产品。 本研究的总体目标是利用最先进的设计和分析流行病学方法 应用于使用全国医疗补助数据定义的大型女性队列， 关于用于治疗妊娠期OUD的药物的比较安全性和有效性的证据。 我们打算采用的具体方法包括倾向评分精细分层，高维 倾向评分调整、替代参考（中止比较）和偏倚分析，以解释 暴露和结局的潜在错误分类以及剩余混杂因素。研究结果如下： 预计将有一个重要的和直接的临床影响，指导临床医生和患者的选择最好的 治疗OUD，以确保母亲及其子女的良好结果。

ABSTRACT The frequency of opioid use disorders (OUD) during pregnancy has increased substantially during the past two decades, reflecting the risk observed in the general population. The current recommendation from guideline groups is that pregnant women with OUD be treated with opioid agonist therapy (OAT). OAT has been shown to improve pregnancy outcomes in women with OUD because it prevents opioid withdrawal symptoms that can be disruptive to fetal well-being and to reduce illicit opioid and other substance use. Methadone has historically been the mainstay of OUD treatment during pregnancy. However, in recent years, buprenorphine use has increased and is now used in approximately equal measure with methadone. Methadone and buprenorphine have different pharmacologic effects. The way in which these treatments are administered is also different. Methadone is dispensed under observation via a federally- regulated opioid treatment program. In contrast, buprenorphine is generally dispensed by prescription in a routine office-based setting. Buprenorphine also comes in two formulations, as a monoproduct and in combination with naloxone, an opioid antagonist, which is intended to deter misuse via injection. Comparative safety and effectiveness data for pharmacologic approaches to the treatment of OUD in pregnancy are very limited. The MOTHER trial demonstrated that buprenorphine is associated with less severe neonatal abstinence syndrome compared to methadone. Data regarding the comparative safety of buprenorphine and methadone with respect to other adverse pregnancy outcomes and the impact on long-term neurodevelopment are few and subject to a number of potential biases and limitations. The comparative effectiveness of buprenorphine and methadone with respect to retention in treatment and impact on adequacy of prenatal care has also not been fully defined. For those prescribed buprenorphine in pregnancy, the use of the monoproduct is generally recommended, despite the higher risk for misuse, because there are few data regarding the safety of the combination product which includes naloxone. The overall goal of this study is to utilize state of the art design and analytic epidemiological methods applied to a large cohort of women defined using nationwide Medicaid data to generate the best possible evidence regarding the comparative safety and effectiveness of medications used to treat OUD in pregnancy. Specific methods that we intend to employ include propensity score fine stratification, high-dimensional propensity score adjustment, alternative referents (discontinuer comparisons), and bias analyses to account for potential misclassification of exposure and outcome and residual confounding. The results of the studies are expected to have an important and direct clinical impact guiding clinicians’ and patients’ selection of the best treatment for OUD in order to ensure a good outcome for mothers and their children.